STING inhibitors sensitize platinum chemotherapy in ovarian cancer by inhibiting the CGAS-STING pathway in cancer-associated fibroblasts (CAFs)

Chemotherapy resistance in ovarian cancer hampers cure rates, with cancer-associated fibroblasts (CAFs) playing a pivotal role. Despite their known impact on cancer progression and chemotherapy resistance, the specific mechanism by which CAFs regulate the tumor inflammatory environment remains unclear. This study reveals that cisplatin facilitates DNA transfer from ovarian cancer cells to CAFs, activating the CGAS-STING-IFNB1 pathway in CAFs and promoting IFNB1 release. Consequently, this reinforces cancer cell resistance to platinum drugs. High STING expression in the tumor stroma was associated with a poor prognosis, while inhibiting STING expression enhanced ovarian cancer sensitivity. Understanding the relevance of the CGAS-STING pathway in CAFs for platinum resistance suggests targeting STING as a promising combination therapy for ovarian cancer, providing potential avenues for improved treatment outcomes. •CAFs promote ovarian cancer cell progression and platinum resistance.•Platinum-induced genomic instability drives DNA transfer from cancer cells to CAFs.•CGAS-STING axis activation in CAFs further promotes platinum resistance of ovarian cancer cells.•High expression of STING in CAFs is related to poor response to platinum and poor prognosis of ovarian cancer patients.•STING inhibitors promote platinum sensitivity of ovarian cancer cells.